title: Cyclic AMP-dependent protein kinase regulates the alternative splicing of tau exon 10: a mechanism involved in tau pathology of Alzheimer disease.
abstract: Hyperphosphorylation and deposition of tau into neurofibrillary tangles is a hallmark of Alzheimer disease (AD). Alternative splicing of tau exon 10 generates tau isoforms containing three or four microtubule binding repeats (3R-tau and 4R-tau), which are equally expressed in adult human brain. Dysregulation of exon 10 causes neurofibrillary degeneration. Here, we report that cyclic AMP-dependent protein kinase, PKA, phosphorylates splicing factor SRSF1, modulates its binding to tau pre-mRNA, and promotes tau exon 10 inclusion in cultured cells and in vivo in rat brain. PKA-Cα, but not PKA-Cβ, interacts with SRSF1 and elevates SRSF1-mediated tau exon 10 inclusion. In AD brain, the decreased level of PKA-Cα correlates with the increased level of 3R-tau. These findings suggest that a down-regulation of PKA dysregulates the alternative splicing of tau exon 10 and contributes to neurofibrillary degeneration in AD by causing an imbalance in 3R-tau and 4R-tau expression.
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Medical School, Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shi
authors.forename: Wei
authors.initials: W
authors.lastname: Qian
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Yin
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
authors.forename: Inge
authors.initials: I
authors.lastname: Grundke-Iqbal
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Gu
authors.forename: Fei
authors.initials: F
authors.lastname: Ding
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
mesh_terms: D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D005091:Exons; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D016874:Neurofibrillary Tangles / Q000737:chemistry; D009687:Nuclear Proteins / Q000737:chemistry; D010766:Phosphorylation; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000737:chemistry; D000068103:Serine-Arginine Splicing Factors; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D016875:tau Proteins; D000068103:Serine-Arginine Splicing Factors; D017868:Cyclic AMP-Dependent Protein Kinases